PROJECT SUMMARY/ABSTRACT Obstructive Sleep Apnea (OSA) is a prevalent disorder with a number of adverse cardiovascular and neurocognitive consequences. However, the leading treatment, positive airway pressure (PAP), is poorly toler- ated by many individuals and thus the development new treatment strategies are critically needed. A number of studies indicate that OSA is caused by the interplay of several phenotypic traits, including a small airway, an oversensitive ventilatory control system, decreased pharyngeal muscle activity during sleep, and premature arousals to a respiratory stimulus. In the previous grant leading up to this continuing renewal, we created methods for measuring these traits as well as a model (termed the ?phenotype model?) that illus- trates the relative contribution of each of these traits to a particular patient's OSA. We believe this model could be valuable for predicting response to PAP-alternatives. At this time, PAP alternatives (oral appliances, surgery, and other devices such as hypoglossal nerve stimulation, etc.) suffer from inconsistent results, and there is no pharmacological treatment for OSA. Howev- er, respiratory control and arousal factors, which are now recognized as having pathogenic roles, provide po- tential new (and untested) pharmacological targets. The objective of this grant is to validate the predictive power of OSA phenotyping, as well as to test the effectiveness of novel pharmacological treatments alone and in combination with existing PAP alternatives such as oral appliance therapy. In Aim 1 of this grant, patients will be ?phenotyped? using the methods developed in the previous grant. We will then perform experiments on the model, e.g., we will treat the model with drugs that change ventilatory control sensitivity and arousal threshold. These simulated treatments will generate a prediction of success or failure. We will then administer the treatments to the patient to see if the model prediction was correct. The treatments that will be given are acetazolamide (for decreasing ventilatory control sensitivity) and eszopiclone (for raising the arousal threshold). These medications will be given simultaneously as well as individually. Thus, an innovative component of this grant is that we will combine medications to maximize efficacy. Aim 2 will test the phenotype model's ability to predict response to oral appliance therapy. The same procedure of phenotyping, followed by simulated treatment on the model to generate a treatment prediction, followed by ex- perimental administration of the treatment to see if the prediction was correct will be used. Predictors of re- sponse to oral appliance therapy remain poor, so Aim 2 fills an important gap in this common alternative treat- ment. Finally, Aim 3 will test the phenotype model's ability to predict response to ?triple therapy? (acetazola- mide + eszopiclone + an oral appliance), which our preliminary data suggest can have a powerful effect on ap- nea severity in the right ?phenotype?. This research could lead to exciting new management strategies for OSA.